tbuckley/cabot-search huggingface dataset:
Abstract 370: Potential of inflammation pro-resolving lipid mediators in controlling cancer cachexia
Authors: Ahmed Attaya, Victoria Haak, Abigail Kelly, Haixia Yang, Eva Rothenberger, Steven D. Freedman, Charles N. Serhan, Dipak Panigrahy
Journal: Cancer Research (2023)

Abstract Most people with advanced cancer exhibit cachexia, a syndrome of progressive weight loss that leads to the death of 20% of patients. The mechanisms underlying cachexia remain poorly understood and, as a result, no treatment has proven effective to date. Cachexia is characterized by systemic hyperinflammation, massive apoptotic cell death (“debris”), and skeletal muscle wasting. Here, we hypothesize that disrupted resolution of inflammation contributes to cancer cachexia, and pro-resolving lipid mediators, specifically novel specialized pro-resolving mediators (SPMs), could control cachexia. SPMs enhance resolution of inflammation by stimulating debris clearance, promoting tissue regeneration, and regulating major immune cell types. In testing our hypothesis, we profiled lipid mediators in a variety of metastatic cachexia models via metabololipidomics and investigated the changes of leukocytes, e.g., T lymphocyte, natural killer (NK), and macrophage cells, in various skeletal muscles (e.g., tibialis anterior and gastrocnemius). Dysregulation of SPMs was identified in different tissues in 5 cachexia models. The SPMs resolvin (RvD)2 and maresin (MaR)1 were reduced in the liver and spleen of colon cancer (CT26)-induced cachectic mice on day 35 post-tumor cell injection and RvD1, RvD2, lipoxin (LXA)4, and MaR1 were dysregulated in Lewis lung carcinoma (LLC)-induced cachectic mice on day 20. Chemotherapy was also found to dysregulate SPMs and induce cachexia in lymphoma (EL4) and ovarian cancer (ID8) mouse models. Ten days post-LLC tumor resection, the RvD1 receptor (ALX/FPR2) KO and RvE1 receptor (ChemR23/ERV) KO mice exhibited a 20-23% loss in body weight compared to WT mice. This shows that neutralizing the pro-resolving activity of RvD1 and RvE1 induces cancer cachexia. Moreover, RvD2 and PCTR (protectin conjugates in tissue regeneration)-2 prevented LLC- and B16F10 melanoma-induced cachexia at 15 ng/day. RvD4, RvD5, MCTR1, or MCTR2 inhibited inflammation-stimulated cytokine storm by counter-regulating the production of CCL3, CCL4, CXCL2, TNF-α, CCL2, G-CSF, and PAI-1. These results indicate that disrupted resolution of inflammation leads to the progression of cancer cachexia, and dysregulated SPMs are potential early markers for cachexia. This study provides a basis for the clinical translation of SPM-directed treatments as a new direction to potentially control cancer cachexia in humans. Citation Format: Ahmed Attaya, Victoria Haak, Abigail Kelly, Haixia Yang, Eva Rothenberger, Steven D. Freedman, Charles N. Serhan, Dipak Panigrahy. Potential of inflammation pro-resolving lipid mediators in controlling cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 370.
Abstract 3695: Mitochondrial uncoupling reverses reductive carboxylation in cancer
Authors: Haowen Jiang, Clifford Jiajun He, Albert M. Li, Bo He, Yang Li, Jiangbin Ye
Journal: Cancer Research (2023)

Abstract When electron transport chain (ETC) activity is inhibited upon hypoxia or when cultured in suspension, reductive carboxylation plays an essential role in supporting tumor growth through converting α-ketoglutarate (α-KG) to citrate, which is converted to acetyl-coenzyme A (acetyl-CoA) for lipogenesis. However, there is no effective way to target reductive carboxylation for tumor therapy. In this study, we use the mitochondrial uncoupler niclosamide ethanolamine (NEN) and BAM15 to reverse reductive carboxylation in cancer cells. Uncoupler treatment activates ETC and increases the cellular NAD+/NADH ratio. Using U-13C-glutamine and 1-13C-glutamine tracers, we discovered that uncoupler treatment accelerates the oxidative TCA cycle and blocks reductive carboxylation, particularly under hypoxia and spheroid culture condition. Uncoupler treatment significantly reduces tumor cell proliferation, survival and sphere formation. In addition, the intracellular acetyl-CoA levels are significantly decreased by NEN treatment. Furthermore, lipidomics analysis showed that NEN treatment reduced fatty acid abundance and altered the lipid composition under both normoxia and hypoxia. Together, these data demonstrate mitochondrial uncoupling redirects the α-KG flux from reductive carboxylation back to the oxidative TCA cycle, highlighting that the ETC activity and NAD+/NADH ratio is the key switch that determines the metabolic fate of α-KG. Reversing reductive carboxylation could be one key mechanism that mitochondrial uncoupler inhibits tumor growth. Citation Format: Haowen Jiang, Clifford Jiajun He, Albert M. Li, Bo He, Yang Li, Jiangbin Ye. Mitochondrial uncoupling reverses reductive carboxylation in cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3695.
Abstract 3700: Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle in prostate cancer
Authors: Kevin Gonthier, Cindy Weidmann, Line Berthiaume, Cynthia Jobin, Aurélie Lacouture, Camille Lafront, Mario Harvey, Bertrand Neveu, Jérémy Loehr, Alain Bergeron, Yves Fradet, Louis Lacombe, Julie Riopel, Éva Latulippe, Chantal Atallah, Michael Shum, Jean-Philippe Lambert, Frédéric Pouliot, Martin Pelletier, Étienne Audet-Walsh
Journal: Cancer Research (2023)

Abstract Background: The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1) but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Methods: Mouse models, in vitro human PCa cell lines, and human prostate organoids were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analysis and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. Results: In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and human patient-derived organoids. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. Conclusions: These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target. Citation Format: Kevin Gonthier, Cindy Weidmann, Line Berthiaume, Cynthia Jobin, Aurélie Lacouture, Camille Lafront, Mario Harvey, Bertrand Neveu, Jérémy Loehr, Alain Bergeron, Yves Fradet, Louis Lacombe, Julie Riopel, Éva Latulippe, Chantal Atallah, Michael Shum, Jean-Philippe Lambert, Frédéric Pouliot, Martin Pelletier, Étienne Audet-Walsh. Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3700.
Abstract 3426: Catalytic degraders effectively address kinase site mutations in EML-ALK oncogenic fusions
Authors: Yang Gao, Baishan Jiang, Hellen Kim, Jianwei Che, Katherine Donovan, John Hatcher, Fidel Huerta, Nicholas Kwiatkowski, Yingpeng Liu, Peter Liuni, Rebecca J. Metivier, Vineeth Murali, Radosław Nowak, Tinghu Zhang, Eric Fischer, Nathanael Gray, Lyn Jones
Journal: Cancer Research (2023)

Abstract Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), is an emerging modality for drug discovery, and theoretically possess catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands guided by computational models. To study the sub-stoichiometric capacity of the degrader molecules, simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than parental kinase inhibitor drugs. Using HiBiT assay to assess the target degradation and NanoBRET for target occupancy, we illustrated the concept of catalytic degradation of EML4-ALK. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant compounded mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer. Citation Format: Yang Gao, Baishan Jiang, Hellen Kim, Jianwei Che, Katherine Donovan, John Hatcher, Fidel Huerta, Nicholas Kwiatkowski, Yingpeng Liu, Peter Liuni, Rebecca J. Metivier, Vineeth Murali, Radosław Nowak, Tinghu Zhang, Eric Fischer, Nathanael Gray, Lyn Jones. Catalytic degraders effectively address kinase site mutations in EML-ALK oncogenic fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3426.
Abstract 2276: Spatiotemporal analysis of metastatic melanoma reveals mechanisms of resistance to immune checkpoint blockade
Authors: Shiyou Wei, Jinho Lee, Marilyne Labrie, Courtney Betts, Lunxu Liu, Lisa Coussens, Meenhard Herlyn, Genevieve Boland, Gordon Mills, Gao Zhang
Journal: Cancer Research (2023)

Abstract The treatment of metastatic melanoma has been revolutionized with the introduction of immune checkpoint blockade (ICB) therapies in the last decade. Despite durable responses exhibited by a subgroup of patients, most of patients do not respond to ICB therapies and the vast majority (60%-90%) of patients experience disease progression within five years. Molecular mechanisms of primary and acquired resistance to ICB are still widely unknown, which warrants further mechanistic investigation. Towards that goal, we used a holistic approach driven by integrated genomic tools to molecularly profile 35 longitudinal tumor specimens at pre-, on-, and post-treatment time points which were derived from seven patients with metastatic melanoma who progressed on sequential ICB therapies, including three responders and four non-responders. We integrated analyses of data generated from RNA sequencing, Whole-exome Sequencing (WES), NanoString nCounter vantage 3D, Cyclic Immunofluorescence (CyCIF), NanoString Digital Spatial Profiling (DSP) and Multiplex Immunohistochemistry (mIHC) platforms to elucidate evolutionary trajectories that occurred in both the tumor and the tumor immune microenvironment (TiME) that may have orchestrated response and resistance to ICB therapies. Simultaneous analyses conducted on genomic, transcriptomic and proteomic levels identified the re-activation of the MAPK pathway as a potential mechanism of resistance to ICB therapies. Spatially-resolved, image-based immune monitoring analysis at single cell resolution revealed that response to ICB is associated with infiltration of immune cells accompanied by induced activities of myeloid, T cells and macrophages in the TiME. In summary, integrated analyses allow us not only to reveal the dynamic co-revolution of both tumor and immune cells in TiME following sequential ICB therapies but also to provide a comprehensive perspective to molecular mechanisms of response and resistance to ICB therapies. A deeper understanding and elucidation of the evolution of mechanisms of response and resistance to ICB therapies will point us to generate hypothesis-driven, potential salvage therapies to overcome resistance to ICB therapies. Citation Format: Shiyou Wei, Jinho Lee, Marilyne Labrie, Courtney Betts, Lunxu Liu, Lisa Coussens, Meenhard Herlyn, Genevieve Boland, Gordon Mills, Gao Zhang. Spatiotemporal analysis of metastatic melanoma reveals mechanisms of resistance to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2276.
Abstract 2710: Developing a novel doppel-targeting antibody-drug conjugate (ADC) for solid cancer
Authors: Ha Kyeong Lee, Byoungmo Kim, Seho Kweon, Jeong Uk Choi, Sang Yoon Kim, Youngro Byun
Journal: Cancer Research (2023)

Abstract The development of anticancer therapeutics has two main objectives: enhancing efficacy and lowering toxicity. Given these goals, an antibody-drug conjugate (ADC), which delivers highly cytotoxic payloads to tumor tissue specifically, is one of the most favorable treatments. ADC is a growing drug delivery technology, with twelve FDA-approved ADCs as of 2022. Most of ADCs in use today target particular molecules for hematologic malignancies. ADCs for solid tumors are relatively in the early stages of development due to the lack of well-defined solid tumor-specific target molecules. To put it another way, the market has an enormous unmet demand for solid cancer-specific ADCs. As seen by recently approved ADCs and ADCs in clinical trials, finding novel targets for solid cancer has drawn a lot of attention in current development trends. Doppel, a prion-like protein, is transiently expressed in the neonatal brain endothelium; in adults, it is exclusively present in testicular cells. In our previous study, we found that Doppel is specifically expressed only in tumor tissues and tumor blood vessels, but not in normal adult tissues; its expression promoted cancerous blood vessel formation. Then, we generated several monoclonal antibodies which target Doppel; the most effective clone was selected. We observed that angiogenesis-related factors were suppressed in the tumor endothelial cells treated with the Doppel-targeting antibody. In addition, we injected the antibody into mouse models and visualized the tumor-targeting efficacy using in vivo imaging system (IVIS); the antibody accumulates in the tumor significantly higher compared to non-targeting IgG. We suggest what we believe to be a novel strategy to target a molecular marker that is altered and overexpressed specifically in tumor tissues and tumor endothelial cells. Based on the above discoveries, we have developed the Doppel-targeting ADC; this drug, according to our hypothesis, will target only cancer cells that express Doppel and result in apoptotic cell death. The ADC has demonstrated remarkable anticancer efficacy in both cell and mouse models, although it is still in the early stages of research. We believe that the enhanced specificity for targeting tumors, the high tumor-to-organ ratio, and the bystander killing effect would make this Doppel-targeting ADC a successful “solid cancer-specific” one. Citation Format: Ha Kyeong Lee, Byoungmo Kim, Seho Kweon, Jeong Uk Choi, Sang Yoon Kim, Youngro Byun. Developing a novel doppel-targeting antibody-drug conjugate (ADC) for solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2710.
Abstract 135: Elucidating tumor evolution in pediatric cancers using stochastic models and mutation accumulation experiments
Authors: Ana Beatriz Massei, Jasmin Jovel Platero, Kyungchan Hong, Sofia Zeledon, Taha Afzal, Hyunjeong Cha, Seung-Hwan Kim
Journal: Cancer Research (2023)

Abstract Ontology-based approaches have been utilized for identifying cancer genes. However, among the thousands of mutations in pediatric cancer genes, accurate prediction of driver genes is one of the biggest challenges. A binary logistic regression model was developed to distinguish pediatric and non-pediatric cancer genes. To build the predictive model, Gene Ontology (GO) enrichment analysis was performed, followed by the PANTHER overrepresentation test, using PANTHER GO-slim, PANTHER, Reactome pathways, and three sets of specific variables, the lists of pediatric cancer genes found in the germline, relapsed, and chemotherapy-resistant cells, respectively. This statistical model was pediatric cancer-specific, confirming known driver genes across cancers. In addition, mathematical models were developed using stochastic differential equation approaches and computational simulations to extend our understanding of the evolutionary dynamics during pediatric tumorigenesis. Moreover, our stochastic models in childhood cancers were validated by mutation accumulation experiments using E. coli strains carrying a mutation in replication restart genes. Finally, this study that elucidates tumor evolution in pediatric cancers could have profound implications for cancer therapy and drug design. Citation Format: Ana Beatriz Massei, Jasmin Jovel Platero, Kyungchan Hong, Sofia Zeledon, Taha Afzal, Hyunjeong Cha, Seung-Hwan Kim. Elucidating tumor evolution in pediatric cancers using stochastic models and mutation accumulation experiments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 135.
Abstract 2280: BG34-200 immunotherapy of advanced melanoma
Authors: Veronique P. Roche, Victor Sandoval, Zachary Senders, Joshua Lyons, Claire Wolford, Mei Zhang
Journal: Cancer Research (2023)

Abstract Background: High levels of myeloid derived cells are characteristic of tumor microenvironment (TME) of advanced melanoma. These cells work with the tumor cells to suppress host development of anti-tumor immune responses, regulate tumor metastasis, and drive cancer drug resistance to virtually all types of therapy. Therefore, methods to disrupt tumor-associated myeloid cell function are actively being sought to find a cure. Goals: Our team has recently developed a plant-derived carbohydrate molecule, BG34-200, that modulates tumor-associated myeloid cells by targeting the cell surface receptor CD11b. In this study, we investigated the immune activation induced by BG34-200-CD11b engagement in the context of advanced melanoma and use the knowledge to develop BG34-200-based combination immunotherapy. Methods: Wild type B57Bl6/J mice were injected with 1.5million B16F10 cells and treated intravenously with BG34-200. Tumor volume and animals survival were monitored, and whole blood was drawn for FACS analysis. Results: We found that BG34-200 IV administration could significantly inhibit tumor growth and improve survival in B16F10 mice with advanced melanoma. Our data supported a model that the entry of BG34-200 into circulating melanoma tumor-associated inflammatory monocytes (TAIMs) could trigger a sequential immune activation: the BG34-200+ TAIM subsets migrated to tumor and differentiated into monocyte-derived dendritic cells (mo-DCs); then, the BG34-200+ mo-DCs migrated to tumor draining lymph nodes where they triggered the generation of tumor antigen specific T cells. Based upon these results, we combined BG34-200 treatment with adoptive transfer of TdLN-derived T-cell to treat advanced melanoma, which significantly improved animal survival and helped tumor-free survivors be resistant to a second tumor cell challenge. Conclusions: The scientific findings from this study will allow us to develop new technology to apply BG34-200-based immunotherapy to patients with advanced melanoma who have not responded to current standard of care therapies with and without immunotherapy. Citation Format: Veronique P. Roche, Victor Sandoval, Zachary Senders, Joshua Lyons, Claire Wolford, Mei Zhang. BG34-200 immunotherapy of advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2280.
Abstract 1076: Targeting EGFR and PI3K pathways with KRASG12D inhibitor overcomes oncogenic dependence in pancreatic cancer
Authors: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Adilakshmi Gandham, Partha Pratim Sarma
Journal: Cancer Research (2023)

Abstract In the U.S., pancreatic cancer is 9th most commonly diagnosed cancer (depending on gender), but the fourth leading cause of cancer death in men and women. FOLFIRINOX or gemcitabine plus nab-paclitaxel have been the standard of care for pancreatic cancer, but late stage prognosis often leads to disease progression of disease, with an overall 5 year survival of 11.5%, in the US, and 9% in Japan. KRASG12D mutant isoform is found in 36% of pancreatic adenocarcinoma patients and hence targeting this major mutation that appear early in the disease may help overcome cancer progression. Several signaling pathways are known to converge on the MAPK and PI3K pathways as effectors of cellular response within the cell. Pancreatic cancer is driven by activating mutations in KRAS, which in turn is expected to activate PI3K signalling through the p110α subunit, indicating that a large proportion of patients could benefit from effective targeting of this pathway. Role of EGFR on the other hand in KRAS-dependent pancreatic cancer progression is not well understood, and cetuximab as single agent has not provided benefit in PDAC patients. Recent studies of KRASG12C inhibitors in combination with EGFR inhibitors have shown clinical benefit in colorectal cancer possibly due to enhanced inhibition of KRAS-dependent signaling or overcoming adaptive feedback mechanisms. This opens an opportunity to investigate combinations of KRASG12D inhibitors with other inhibitors of MAPK and PI3K pathways. Here we report a data for 40-point combination dose response matrix combining VRTX153, a novel and highly selective inhibitor of KRASG12D with Alpelisib (a p110α inhibitor) and an EGFR inhibitor using MTT assay. Effect on downstream markers such as pERK, pEGFR and pAKT is being investigated. In vivo pharmacological effect of these agents will be investigated in the due course of development. Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Adilakshmi Gandham, Partha Pratim Sarma. Targeting EGFR and PI3K pathways with KRASG12D inhibitor overcomes oncogenic dependence in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1076.